Journal of Medical Microbiology (2014), 63, 892895

DOI 10.1099/jmm.0.070060-0

Association between HACEK bacteraemia and

endocarditis
Haur Sen Yew,1 Stephen T. Chambers,1,2 Sally A. Roberts,3
David J. Holland,4 Kylie A. Julian,4 Nigel J. Raymond,5 Justin Beardsley,5
Kerry M. Read6 and David R. Murdoch1,2
Correspondence

Haur Sen Yew

yewha550@gmail.com
David R. Murdoch
David.Murdoch@cdhb.health.nz

Christchurch Hospital, Christchurch, New Zealand

University of Otago, Christchurch, New Zealand

Auckland City Hospital, Auckland, New Zealand

Middlemore Hospital, Auckland, New Zealand

Wellington Hospital, Wellington, New Zealand

North Shore Hospital, Auckland, New Zealand

Received 29 October 2013

Accepted 28 March 2014

We retrospectively examined medical records of 87 patients with bacteraemia caused by

members of the HACEK group (Haemophilus parainfluenzae, Aggregatibacter
actinomycetemcomitans, Aggregatibacter aphrophilus, Aggregatibacter paraphrophilus,
Cardiobacterium spp., Eikenella corrodens and Kingella spp.) to determine whether endocarditis
was present, as defined by the Duke criteria. The overall positive predictive value (PPV) of HACEK
bacteraemia for endocarditis was 60 %. The PPV varied with different HACEK species from 0 %
(E. corrodens) to 100 % (A. actinomycetemcomitans).

The Duke criteria are an important diagnostic tool for

infective endocarditis (Li et al., 2000). The isolation of a
pathogenic micro-organism from blood cultures is a major
criterion provided that two important features are met,
namely the identification of a typical species of microorganism and the presence of persistent bacteraemia.
Persistent bacteraemia is defined as either (i) two positive
blood cultures drawn .12 h apart, or (ii) a positive result in
all of three or most of four or more separate blood cultures,
with first and last specimens drawn at least 1 h apart.

METHODS

The HACEK group of bacteria (Haemophilus parainfluenzae,

Aggregatibacter actinomycetemcomitans, Aggregatibacter aphrophilus, Aggregatibacter paraphrophilus, Cardiobacterium
spp., Eikenella corrodens and Kingella spp.) are wellrecognized causes of infective endocarditis and are infrequently isolated from blood cultures of patients without
endocarditis. Given the strong association between HACEK
bacteria and endocarditis, we hypothesized that just one
positive blood culture may be sufficient to make a diagnosis
of HACEK endocarditis. The principal aim of our study was
to determine the positive predictive value (PPV) of HACEK
bacteraemia for the presence of endocarditis.

The clinical notes of all cases were reviewed and the relevant clinical
information transcribed onto a standard data sheet. The clinical data
obtained included patient demographics and co-morbidities, number
of positive blood cultures, echocardiography findings, antibiotic
therapy and mortality at 1 year. During review of the clinical notes,
the diagnosis of endocarditis was determined in accordance with the
modified Duke criteria by an infectious diseases physician or trainee,
and was subsequently recorded in the data sheet. All data sheets were
then analysed by H. S. Y., S. T. C. and D. R. M.

Abbreviations: HACEK, Haemophilus parainfluenzae, Aggregatibacter

actinomycetemcomitans, Aggregatibacter aphrophilus, Aggregatibacter
paraphrophilus, Cardiobacterium spp., Eikenella corrodens and Kingella
spp; PPV, positive predictive value.

892

A case was defined as a patient with at least one positive blood culture
with a HACEK bacterium. Definitions of definite and possible infectious
endocarditis were according to the Duke criteria (Li et al., 2000).
Cases were identified from May 1979 to February 2011, through
electronic databases from microbiology laboratories at Christchurch
Hospital (Christchurch, New Zealand), Auckland City Hospital
(Auckland, New Zealand), Middlemore Hospital (Auckland), North
Shore Hospital (Auckland) and Wellington Hospital (Wellington,
New Zealand).

Ethics approval was obtained from the New Zealand Ministry of

Health Multi-region Ethics Committee.

RESULTS
Overall, 87 cases of HACEK bacteraemia were identified, of
which 81 were from the period between 1995 and 2010. In
total, 52 of the 87 cases had endocarditis (PPV 60 %). The
characteristics of the cases by HACEK species are shown in

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HACEK bacteraemia and endocarditis

Tables 1 and 2. The PPV of bacteraemia for endocarditis

varied with HACEK species, ranging from 100 % for A.
actinomycetemcomitans and A. paraphrophilus to 0 % for E.
corrodens.
The eight cases of H. parainfluenzae bacteraemia who did
not have endocarditis had the following foci of infection
identified: meningitis (one case), appendicitis (one case),
epidural abscess (one case), urosepsis (one case), presumed
contaminant (one case) and unknown focus (three cases).
Of the 18 cases of A. actinomycetemcomitans bacteraemia,
all had a diagnosis of endocarditis. Three cases had either
reinfection or relapse (Chu et al., 2005; Tornos et al., 2011).
The first case had a mechanical aortic valve and diabetic
nephropathy requiring dialysis, was treated with 42 days of
ceftriaxone, became reinfected 9 months later and died.
The second case had a mechanical mitral valve and had
reinfection 3 years later. This was treated with 42 days of
ceftriaxone but relapsed 11 days later, before a curative
reoperation with mitral valve replacement was performed.
The third case had a pulmonary artery homograft valve
replacement in the setting of a congenital ventricular septal
defect and was treated with 42 days of ceftriaxone but
relapsed 6 months later. A. actinomycetemcomitans was
cultured during each repeat episode and is the only
HACEK bacterium associated with repeated endocarditis in
this study.
Five of the nine A. aphrophilus cases were diagnosed with
endocarditis, and other foci of infection identified were
sacroilitis (one case), pneumonia (one case), presumed
contaminant (one case) and unknown focus (one case).
Among the eight cases of Cardiobacterium bacteraemias, six
were Cardiobacterium hominis, one was Cardiobacterium
valvarum and one was not identified to the species level. Six
of the seven cases of Cardiobacterium endocarditis affected
the aortic valve. The single case without endocarditis had
radiographic pneumonia, which was successfully treated
with 10 days of antibiotic therapy. This patient also had a
bioprosthetic aortic valve replacement. Delayed transthoracic echocardiogram 4 months later and transoesophageal

echocardiogram 7 months later showed no evidence of

endocarditis.
None of the 11 cases of E. corrodens bacteraemia was
diagnosed with endocarditis, although echocardiography
was performed in only three cases. Four had cancer
(oesophageal cancer, colon cancer, diffuse large B-cell
lymphoma or metastatic prostate cancer), one had endstage alcoholic liver disease and three had acute appendicitis.
The foci of infection identified were appendicitis (two
cases), gingivitis (one case), oesophagitis (one case), liver
abscess (one case), mediastinitis (one case), gastrointestinal
tract (one case), central line infection or contaminant (one
case), presumed contaminant (one case) and unknown
focus (two cases). Six (55 %) had died at 1 year.
Among the 19 cases of Kingella bacteraemia, 17 were
Kingella kingae, one was Kingella denitrificans and one was
not identified to the species level. Thirteen cases were aged
between 0 and 3 years and the remaining six cases were
ages 2161 years. Among the paediatric cases, five (38 %)
were diagnosed with endocarditis, and three of these cases
were complicated by cerebral emboli. Among the adult
cases, three (50 %) were diagnosed with endocarditis and
none of these suffered from embolic complications. Of the
19 Kingella cases, nine (47 %) did not have echocardiography performed. Of the 11 cases that did not have a
diagnosis of endocarditis, the foci of infection identified
were septic arthritis (three cases), stomatitis (two cases),
pharyngitis (one case), presumed contaminant (one case)
and unknown focus (four cases).
If a single blood culture with a HACEK bacterium was
considered as a major Duke criterion for endocarditis and
applied to our cases, eight cases (three Kingella spp., three
H. parainfluenzae and two E. corrodens) without endocarditis would be reclassified as possible endocarditis, and five
cases (four A. actinomycetemcomitans and one H. parainfluenzae) of possible endocarditis would be reclassified as
definite endocarditis.
Of the 87 cases, 60 were investigated with an echocardiogram. Of these 60 cases, 21 had only a transthoracic

Table 1. Characteristics of the cases of HACEK bacteraemia and the PPV for endocarditis
Micro-organism

H. parainfluenzae
A. actinomycetemcomitans
A. aphrophilus
A. paraphrophilus
Cardiobacterium spp.
E. corrodens
Kingella spp.
Total

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No. cases (%)

18
18
9
4
8
11
19
87

(20.7)
(20.7)
(10.3)
(4.6)
(9.2)
(12.6)
(21.8)
(100)

Median age in
years (range)
38.5
45.5
51.0
55.0
55.0
67.0
1.0
45

(067)
(2076)
(1885)
(3858)
(4585)
(1881)
(057)
(085)

Sex
(male/female)

No. positive
blood cultures
(mean)

11/7
12/6
6/3
4/0
7/1
9/2
11/8
60/27

2.4
3.3
2.7
2.8
4.5
1.0
1.8
2.5

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Total no. endocarditis

cases (definite/possible)
by Duke criteria
10
18
5
4
7
0
8
52

(7/3)
(9/9)
(3/2)
(4/0)
(5/2)
(7/1)
(35/17)

PPV (%)

55
100
55
100
88
0
42
60

893

H. S. Yew and others

Table 2. Characteristics of the cases of HACEK endocarditis

Valve type: A, aortic; M, mitral; P, pulmonary; T, tricuspid.
Micro-organism

No. cases

Valve
A

H. parainfluenzae
A. actinomycetemcomitans
A. aphrophilus
A. paraphrophilus
Cardiobacterium spp.
E. corrodens
Kingella spp.
Total

10
18
5
4
7
0
8
52

3
5
0
4
6
0
1
19

(30 %)
(28 %)
(100 %)
(86 %)
(13 %)
(36 %)

M
4
8
2
0
1
0
5
20

(40 %)
(44 %)
(40 %)
(14 %)
(63 %)
(38 %)

A and M
2
3
1
0
0
0
0
6

(20 %)
(17 %)
(20 %)

(12 %)

echocardiogram and 15 had a diagnosis of endocarditis,

whereas 39 cases had a transoesophageal echocardiogram
and 37 of them had a diagnosis of endocarditis. Twentyfive cases did not have an echocardiogram performed and
none of them had a diagnosis of endocarditis. There were
two cases where data regarding echocardiography were
unavailable.

DISCUSSION
To our knowledge, this is the first study describing the PPV
of HACEK bacteraemia for endocarditis. Overall, 60 % of
cases of HACEK bacteraemia had endocarditis, although
this varied by HACEK species.
A major finding from our study is that detection of A. actinomycetemcomitans in blood cultures was always associated
with endocarditis. Previous reports of invasive A. actinomycetemcomitans infection have also found a high prevalence
of endocarditis. Wang et al. (2010) described 10 patients
with A. actinomycetemcomitans bacteraemia, of whom eight
were diagnosed with endocarditis, one with pneumonia
and one with periauricular osteoradionecrosis in the setting
of nasopharyngeal carcinoma. The case with pneumonia
had transthoracic (but not transoesophageal) echocardiography performed, whereas the case with osteoradionecrosis did not have echocardiography performed. Paju et al.
(2003) also described a series of patients with non-oral
A. actinomycetemcomitans infections, three of whom had
bacteraemia; one was diagnosed with endocarditis, one
with septicaemia and one with fever of unknown origin. It
was unclear what diagnostic measures were undertaken in
these patients.
A. actinomycetemcomitans is a major causative agent of
periodontal disease, particularly a condition known as
localized aggressive periodontitis (Henderson et al., 2002),
and this is due to the bacteriums ability to express a host
of virulence factors. These include factors that promote
colonization and persistence in host tissues, factors that
interfere with host defences, factors that destroy host tissues
894

Valve type
P

1
1
0
0
0
0
1
3

(10 %)
(6 %)

(12 %)
(6 %)

Not clear

Prosthetic

0
0
0
0
0
0
1 (12 %)
1 (2 %)

0
1 (6 %)
2 (40 %)
0
0
0
0
3 (6 %)

2
14
1
2
4
0
1
23

(20 %)
(78 %)
(20 %)
(50 %)
(57 %)
(13 %)
(44 %)

Native
8
4
4
2
3
0
7
29

(80 %)
(22 %)
(80 %)
(50 %)
(43 %)
(87 %)
(56 %)

and factors that inhibit repair of host tissues (Fives-Taylor

et al., 1999). A number of these virulence factors are likely to
be implicated in the pathogenesis of A. actinomycetemcomitans endocarditis. Examples are LtxA protein (a leukotoxin
that causes leukocyte apoptosis), cytolethal distending toxin
(a cell-cyle-inhibitory protein), Omp34 protein (an Fcbinding protein) and Flp-1 protein (a fimbrial protein that
enables tight auto-adhesion) (Henderson et al., 2002).
The isolation of Cardiobacterium spp. from blood was also
strongly associated with endocarditis in our study. This is
not surprising given that almost all reported cases of Cardiobacterium spp. infection have endocarditis (Graevenitz et al.,
2007; Steinberg & Burd, 2010). One review found 61 cases of
endocarditis among 63 cases of bacteraemia (Malani et al.,
2006). The predilection to affect the aortic valve is also
consistent with the experience of others (Brouqui & Raoult,
2001).
In contrast, isolation of E. corrodens in blood was not
associated with a clinical diagnosis of endocarditis in our
study. Sheng et al. (2001) described a series of 43 patients
with invasive E. corrodens infection, of whom eight were
bacteraemic. Only one patient was diagnosed with endocarditis. Interestingly, among their patients, 15 (35 %)
had underlying malignancies. Due to the lack of echocardiography data in our study, we are unable to draw firm
conclusions regarding the PPV of E. corrodens bacteraemia
for endocarditis. The lack of these data may reflect the
severe underlying co-morbidities found in this group and
the reluctance to investigate further.
Although only 38 % of the paediatric cases of Kingella
bacteraemia in our study were diagnosed with endocarditis,
this is a higher proportion than has been reported previously. Dubnov-Raz et al. (2008) described 42 children
with K. kingae bacteraemia, of whom only 16 underwent
echocardiography and four were diagnosed with endocarditis. A subsequent study of 296 paediatric cases of invasive K.
kingae disease found 169 cases of skeletal infection (48 were
bacteraemic), 140 cases of occult bacteraemia, eight cases
of endocarditis and four cases of bacteraemic pneumonia

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Journal of Medical Microbiology 63

HACEK bacteraemia and endocarditis

(Dubnov-Raz et al., 2010). Interestingly, 95 % of these

infections were in children younger than 4 years old, which
is consistent with our findings.

Dubnov-Raz, G., Scheuerman, O., Chodick, G., Finkelstein, Y.,

Samra, Z. & Garty, B. Z. (2008). Invasive Kingella kingae infections in

A. paraphrophilus bacteraemia was also highly predictive of

endocarditis in our study, but the number of cases was small.
Approximately half of the H. parainfluenzae, A. aphrophilus
and Kingella spp. cases had a diagnosis of endocarditis.
Although detection of these organisms in blood cultures was
not always predictive of endocarditis, this remained the
most common diagnosis.

Dubnov-Raz, G., Ephros, M., Garty, B. Z., Schlesinger, Y., MaayanMetzger, A., Hasson, J., Kassis, I., Schwartz-Harari, O. & Yagupsky,
P. (2010). Invasive pediatric Kingella kingae infections: a nationwide

The major limitations of our study are the reliance on

retrospective assessment of case notes for data collection
and the lack of echocardiographic data from quite a number
of cases. Consequently, we may have underestimated the
proportion of cases with endocarditis. HACEK bacteraemia
is relatively uncommon, and the number of cases for some
HACEK species was small, thereby affecting the precision of
our PPV estimates. Lastly, the study was conducted in the
New Zealand population only, which may limit applicability
to other populations.
In conclusion, we have preliminary evidence to suggest that
isolation of A. actinomycetemcomitans from a single blood
culture should be considered a major Duke criterion for
the diagnosis of infective endocarditis. The same may also
apply to Cardiobacterium spp. and A. paraphrophilus. More
data are required to confirm these findings.

ACKNOWLEDGEMENTS
We gratefully acknowledge Dr Susan Taylor, Dr Michael Humble,
Esther Lau and Phil Tough for their assistance with identifying cases
of HACEK bacteraemia for the study. The authors declare no conflicts
of interest.

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